Viva La France

 

I actually have some really great news!

 

Our natural history study for San C was finally approved by the French Committee for the Protection of Persons and CNIL!  You can find the study on NCT#05825131

 

Press release

 

I am over the moon excited to finally be green lighted to start this study. It’s a dream come true! Since we first formed JJB in 2009 our advisors stressed the importance of a natural history study.  We were advise to document the course of the disease and the data could potentially serve as the control arm in a clinical trial.  This is the first ever NHS for MPS IIIC.

Site Initiation Visit, November 6th 2024

 

 

 

Convincing the FDA to accept natural history as a control arm remains to be seen. Change is happening at the FDA; they are finally starting to understand the plight of the ultra-rare. The FDA told us to conduct a natural history study, we have it right there in our meeting minutes.  There is one person at the FDA that is driving the issue, Peter Marks.

 

Dr. Marks is the director of CBER, this is the wing of the FDA that will review our gene therapy program. Last year, I had a nice face to face with Dr. Marks and shared with him the hurdles that San C would have in an interventional trial. I explained to him that San C was even more rare than A and B; diagnosing a child under the age of four without an older sibling being diagnosed first is virtually unheard of. Jonah being an exception.

 

Dr. Marks listened as I explained that the kids in our trials would be symptomatic, they would already have brain damage and the go-to cognitive assessments that the FDA reviewers trusted are not appropriate for evaluating our kids. Furthermore, our kids can be stable for years. I implored to him that it would be highly unlikely to show clinically meaningful change in a two-year trial and there was no way we could afford a trial that lasted more than 2 years. My ask was for him to encourage his reviewers to embrace the power bestowed on them and grant Accelerated Approval (AA).  AA is given by the FDA when a drug demonstrates that it reduces a disease-causing biomarker. In our case that biomarker is Heparan Sulfate (HS). HS builds up in the lysosome of our children’s cells. AA allows the drug company to start selling the drug before full approval.  This allows kids not in the trial to be treated and gives the drug company some revenue to finish out their trial.  Push back from the FDA stems from concern that some drug companies will take advantage of AA. Just recently Ultragenyx received AA for its gene therapy program for the treatment of San A!  This sets precedence for Phoenix Nest to follow.

 

With that said we still must find assessments that show meaningful change. I explained the symptoms of Sanfilippo to Marks and pointed out that we don’t have many endpoints that can be readily measured. Marks advised me to show the reviewers functional improvement. That’s where the video assessment portion of our natural history study comes into play.

 

We created a special protocol that will be used to assess children’s functional abilities at home.  The protocol captures the children performing activities of daily living (ADL’s).  Parents download a medical application onto their phone, consent to the study and follow the directions provided to them. The tech was designed by Aparito and is stored on HIPPA/GDPR compliant software.  We named the app C-RARE, get it C as in Sanfilippo type C, C as in see. RARE stands for Recording Application of Real-world Evidence.

 

Sanfilippo kids have a really hard time sitting still and paying attention to a cognitive assessment administered in the clinic is not practical.  With C-RARE we will capture the child’s true abilities in the comfort of their home. They’ll also visit the clinic and have numerous assessments done.

 

I must share with you the absolute nightmare of trying to get our NHS approved by the French ethics committee and CNIL. Let this story be a lesson for those that want to do the same. 

 

Starting from the beginning.

 

In May of 2022 I went to France and met up with three French type C families at a family conference hosted by the patient organization VML.  France is the perfect country to launch our first NHS site. It has the largest known patient population (except for Brazil) and a compassionate doctor who cares for patients living with San C. Dr. Guffon, is also experienced in running MPS trials.  With the support of Dr. Guffon and help from Aparito, I pitched VML to help fund our NHS in France. The pitch was successful.

 

I went home and started working with Fortrea, our contract research organization. Fortrea manages our trial, they do the medical writing, submissions and regulatory oversight.  We finished the protocol and informed consents and submitted to the French ethics committee in September of 2022. We didn’t receive approval until October 2024! Every time I talk to a parent they ask how long until we can go to interventional trial? Approval for a non-interventional trial took 2 years. I can only imagine how long it will take to get a protocol approved for an interventional trial. I want to start the regulatory process now!

 

The ethics approval process in France is different than the US, in France you’re sent to one of 13 different committees. It’s just luck of the draw. You then get two chances to answer two rounds of questions from the committee. If you don’t answer their questions to their satisfaction, you receive an ‘unfavorable’ opinion and are sent to a different committee to re-submit. If after two unfavorable submissions, you must start all over with a new protocol.  

 

The committees don’t even look at the questions or responses from the other committees, as they are completely independent and therefore have their own opinions. So, expect a whole new round of questions.

 

Our first committee was obsessed with us collecting medical records from families of deceased children. They wanted us to take that out of the protocol.  If we insisted on keeping it in the protocol, then we needed to have a clinical psychiatrist to help the families through the trauma of being asked to donate the records of their deceased child’s medical records. They said that it would be too hard on the families to be asked to participate in the study. They didn’t know it was a parent that designed the study.  The reviewers also didn’t grasp why patients would want to participate in a study that didn’t offer a treatment. They questioned the importance for using so many cognitive and physical assessments. They didn’t have any concept of the hurdles that sponsors creating treatments for ultra-rare, slowly progressing, pediatric diseases were up against.  

 

We had to explain everything in writing.  They refused to talk to us on the phone and allow us to educate them on the importance of a NHS and why we had included so many assessments. We explained all this, then they came back and asked us a whole new set of questions. They set us up to fail. We couldn’t get through another set of questions without exhausting our two tries. They asked us to create a table within the protocol that broke down and explained each assessment and what it was measuring.  We of course had already done this within the protocol in paragraph form. We asked them to be more specific in what they were asking, and they responded we just told you and that was it. So, we created the table and added it to the protocol.  They came back and said we didn’t answer their question correctly and they kicked us to the curb. There were 24 questions in the first committee’s response. We had 2 weeks to respond to all of them and turn it around and have it back translated to French. The process is epic.

 

The second committee was obsessed with the informed consents. They didn’t like the tone in which the assessments were written.  For instance, the infant informed consent was not dummied down to the point that it was baby talk. The adolescent consent was too babyish, and we needed to be more specific on potential risks of blood draw, CSF draw and MRI’s. Giving statistics on how often a CSF draw could cause a headache or the chances of bruising from a blood draw. Remember these patients can’t read or comprehend what the study is about, and the parents will ultimately consent to the study.  In all we had to write 7 different informed consents/assents, each one tailored to the age range of the patient that would be ‘reading’ it. They were obsessed with pregnancy tests; would it be a blood or urine test?  Where would we store the blood or urine? How would we address the pregnancy results with the patient and their caregiver? This review team didn’t act as if they knew that the patients had profound brain damage and would not be able to consent to intercourse, let alone read a consent form. At the end of the day, they refused us because they didn’t agree with the terminology, we used to describe the caregiver of a patient that was a ward of the state.

 

We had to start over, changing the name of the protocol, the study number and making the protocol slightly different so that it appeared to be new. You could imagine how mad I was. I screamed profanities into the emptiness of my office. The person that shares a wall with me won’t make eye contact with me when he sees me in the hall.

 

I informed the patient organizations that were supporting the study; Sanfilippo Sud and VML and sent them the comments. Guilhain, the president of Sanfilippo Sud and one of the co-founders of Phoenix Nest and HANDS took our plight to the French Ministry of Health.

 

Guilhain read that Oliver Veran the government spokesperson and previous minister of health would be speaking at an event near him. Guilhain went to the event, he worked his way through the crowd and grabbed Veran’s attention. He was given five minutes to speak to Dr. Veran, Veran was moved by our story and put him in touch with the current Minister of Health.  Guilhain, was then able to walk the representative through the ethics approval process and share with them the comments of the first two committees.  He was told that they couldn’t tell the ethics committee what to do, but they would certainly investigate it.

 

We resubmitted in July; we had to wait out all of August because everyone in France goes on holiday in August. They reviewed our protocol and informed consents on the 9^th of September and turned around and gave us comments within two days of reviewing our submissions. They asked a couple of minor questions; they didn’t ask us to change anything on the protocol. They did ask us to shorten and combine the informed consents that they were too long for a patient that didn’t have the cognitive capacity to read them and there were too many of them. Go figure…. We fixed the consents and that was it, 2 days later we were given approval.

 

We lost two years and tens of thousands of dollars trying to satisfy the ethics committee. This family here have 2 children, the youngest is the youngest known child in the world. We just lost two years of his life.  Nice work people.

 

We are now in the process of opening a second site in the US at UT Southwestern, Texas. The process is intense as well, we have been warned that it will most likely take 6 months. Our submission date is December 23^rd, with any luck we will be enrolling this summer.

 

Meanwhile, the pre-clinical safety and dose ranging mouse study we started last year is wrapping up. There was concern at the beginning because our mouse model ended up being less severe than we had anticipated. It took longer for us to see behavioral changes in the animals. Fortunately, everything fell into place. Our mice finally got sick, and we were able to show behavioral and survival improvement between our treated and nontreated mice. All the mice are being taken down now and will be shipped off to Australia, where Dr. Fuller will be doing the all-important work of analyzing Heparan Sulfate levels. Woohooo! Next week will kick off the start of the toxicology study. While that study is underway, we hope to write and take our clinical package to the FDA for comments. We need substantial funds for the clinical writing and the clinical grade vector production. Our current NIH grant isn’t enough to pay for the work. With the toxicology data and the data from the mice behavioral and dosage study, combined with the HS analysis we will write yet another grant. I’m confident that we will score high enough to be awarded the grant. Unfortunately, the process of writing and waiting for the NIH grant to be funded will add an extra year to our timelines. Secondly, I’m terrified that the new administration will cut funding to the NIH and we won’t be able to secure federal grants.  

 

I’m very happy with our progress and I expect that we will soon have a clear picture of our path to the clinic. I look forward to updating you in another 6 months.  

 

If so, moved you can help

keep our studies on track by donating to my Giving Tuesday fundraiser.

 

 

 

 

Mutated genes, traumatic labor, and birth defects do not discriminate

I love Jonah and our life together. In this post today I hope to raise awareness for the people with developmental disabilities and those that love and care for them. 

I'm not complaining about my lot in life. 

In situations like ours one parent either quits their job to stay at home with their child or they hire an aid to cover the hours that they're not home. Many families need an extra hand throughout the day and at night.  The out of pocket costs are not realistic for most families. Imagine paying for your child's daycare for the rest of their life. Staying home ends up being the better option.  Which means the family loses a second income.  Which in turns prohibits the family from saving funds for their disabled child's future medical needs or their healthy child's college education. 

"The shape they're in, all the expenses, maybe those kinds of people should just die." -Donald Trump

Sanfilippo syndrome has made Jonah who he is. Jonah brings Jeremy and I tremendous joy and happiness.  Our love for him is profound and we can't imagine him any other way.  To say I wish Jonah didn't have Sanfilippo syndrome is to say I wish Jonah wasn't Jonah.  I don't want Jonah to die and for that I wish he didn't have Sanfilippo. I don't want his body and brain to be ravaged by seizures.  For the dementia to rob him of the ability to walk, talk and eat on his own.  I don't want the sleepless nights to ever start.  I don't want him to have to fight one bought of pneumonia after the next until his lungs give out and his brain shuts down.  No matter what happens... I know that Jonah will always know who Jeremy and I are and he will know that we love him. 

I just want Jonah to live his best life possible.  He deserves that, he deserves the same access to an education, housing, healthcare and services that a healthy child has. To be accepted in his community and treated like a human being by society.

Jonah is aware that he's not like the typical kids at the local playground, he's gotten past that and steers clear of the kids that point out his disabilities. He's never indicated that he's jealous or upset that he can't do the same things they can do. He loves meeting new people, traveling, hosting parties, playing soccer and hanging out with me and his dad. His private school is the best, Jeremy and I feel like we won the lottery with his school. Jonah is happy and we're content being happy that he's happy.

He doesn't recognize you.  Maybe you should just let him die and move down to Florida"- Donald Trump

If I had known during my first trimester of my pregnancy that Jonah had a terminal illness, would I have terminated the pregnancy? I do not know. But if I was pregnant with a second child after the first child was diagnosed and found out that my fetus was also affected, I would most likely terminate. Because our society works against people with disabilities.  The hardships of caring for two terminally ill children would have been financially disastrous. We would have struggled our entire lives trying to make ends meet and provide our children with the necessities of life. 

Today our rights to an abortion are being taken away.  On one hand Trump says that kids like Jonah should just die and on the other he would allow states to deny us the right to terminate a fetus that carries a disease that causes profound cognitive disabilities and need for lifelong medical attention.

Trump appointed three of the nine justices on the Supreme Court, giving the court the conservative majority it needed to overturn Roe V Wade. He says "I was proudly the person responsible for the ending of something that all legal scholars, both sides, wanted and in fact demanded be ended. Roe V Wade, they wanted it ended," -Donald Trump video posted on Truth Social April 8th

Jonah is pushing 18 and we have started the ball rolling for when that days comes. Once he turns 18 we must be legally granted guardianship in order to make decisions for him and to take him to his doctor appointments.  We recently applied for and were granted services through OPWDD Office of People with Developmental Disabilities'.  However, Jonah still needs to be approved for Medicaid before we can access the services, we're working on this process now. OPWDD will help us hire an aid for him and find an adult daycare program for him. During Trump's administration Trump did everything he could to try to abolish the Affordable Care Act which protects Medicaid programs like NYs OPWDD. When the day comes that Jonah can't walk we will need help with medical equipment. For instance we will need special equipment to get him in and out of a tub, I'm thinking we'll need to move to a place with a walk in shower and perhaps a bidet, to clean his bottom. I think I have mentioned Sanfilippo diarrhea in the past.  Wheelchair, safe-bed, seizure monitoring equipment etc. We're going to need all the help we can get and if Trump had his way he'd let Jonah die.

You might think this doesn't affect you, so why should you care. Don't jinx yourself, mutated genes, traumatic labor, and birth defects do not discriminate. You could have passed your disease causing mutation to your children, you just don't know yet. Your new baby grandson could have a stroke during delivery or be deprived of oxygen and be born with brain damage. 

Speaking now to a different kind of childhood death that Trump glazes over. Shortly after taking office, Trump signed into law a bill that reversed an Obama-era regulation that made it harder for people with mental illness to purchase guns.  Trump is incredibly lucky that the kid missed. I wonder how far Thomas Crooks imagined he would get? Shimming up a a building in broad daylight with a rifle hanging over his shoulder and cops all around. Mind blowing, pun intended.  Our society grossly ignores mental health distress. It saddens me to know that Thomas was relentlessly bullied in school.  Perhaps the shooting would never have happened if Thomas had been protected and helped by the adults entrusted to care for him.... Or if he didn't have easy access to a gun... Gun control Donald Trump!  The irony is dumbfounding. Did you know that the number one cause of death for children between 1-19 is from gun related incidences?

I haven't stopped work to take the time and write about the accomplishments and progress that Phoenix Nest has made towards a treatment this past year. I feel bad about that and I hope to get a work post out soon.  Right now I feel compelled to plead with those planning to vote for Trump to think about Jonah and the tens of thousands of families in our position. 

Trump could destroy everything that myself and my rare disease community have worked so hard for.  He can limit NIH funding, he can slow FDA drug approvals, he could take away Medicaid programs, limit funds to special education and influence drug reimbursement. He does not support my son, my small business or my community of families of developmentally disabled children. Based on his first term we have reason to believe that all our programs are in jeopardy. FYI, these are just  concerns for todays post.

The moment that bullet grazed Trump's ear I thought we were done for. The guy would become untouchable and for a few weeks it seemed that way. I started thinking about how I would tolerate the next four years. Our natural history study will take 4 years to complete, I'll just pour myself into work and not look up. Then Biden rose to the occasion and dropped out of the run for office. To my delight Kamala Harris was selected as the new democratic presidential candidate. I feel that a huge weight has been lifted from my shoulders. 

I'd like to acknowledge a fellow Sanfilippo parent that is fighting to raise awareness and protect the rights for those with disabilities through her Instagram account, you can find Noel and Logan Pacl at love_logan007

There are a handful of other courageous Sanfilippo parents raising awareness through social media. I praise them for their dedication and tough skin. My JJB Instagram account is now perkyplantslivehere. I post about my beloved office plants, you can marginalize my plants I can deal with that. I just can't easily or gracefully respond to or rebound from the hurtful posts that strangers made on my personal and JJB posts regarding rare disease.

I'm dedicating this post in loving memory to Jan, Jonah's adoring grandma. Jan's affection for Jonah was unwavering she absolutely adored him. Watching her engage with Jonah was heartwarming. Jan will be deeply missed by all those that loved her. We lost her too soon. I know that Jan would have appreciated this blog. RIP grandma Jan.

Jonah's 16th Birthday 

It's been a hot minute

Long time no write.

When you get the alert in your inbox that I have posted a blog do you think to yourself: Oh boy which one of her friends lost their child? Or what is she fundraising for now? It's the truth and it's one of the reasons I don't write very often. That and I just can't find the time.

I'm going to rip the band aid off. It was Pol that died. He died on April 5th after a long stint at the hospital fighting off one bout of pneumonia after another until his lungs were too weak to keep going. Pol had just turned 18. His mother Belen worked incredibly hard to raise funds to help fight our children’s fate. Belen is one of the founders of HANDS, PN and Sanfilippo Barcelona. Belen is like family to me; Pol and Jonah could be brothers. They’re so much alike, both devilishly handsome, infectious smiles and gregarious personalities. Momma’s boys to the end.

Belen found me right after Pol was diagnosed, she came to New York and attended JJB’s IIIC investigator meeting at Columbia. The meeting where we kicked off our gene therapy research program. She raised over a hundred thousand dollars for our research, by teaming up with football superstar Andrés Iniesta. Remember when Jonah and I dropped everything and took a redeye to Spain to meet Belen at a press conference with Andrés? It was for the launch of a fan book about his team Heroés Del Deporte with proceeds dedicated to Sanfilippo Barcelona. Jonah and I walked into the pressroom, not knowing what was behind the door. Belen yelled our names, and the crowd of photographers and news reporters turned their cameras on us. I had never seen anything like it. Wall to wall reporters. The next morning Jonah and I went to the airport the news stands at the airport were filled with papers highlighting the press conference. I picked up one of the many papers with Andrés, Jonah, and I on the front page and gasped. Our 15 minutes of fame. The press conference was a few months after Andrés scored the winning goal for Spain during the 2010 World Cup. What a trip!

We were all so full of hope back then. Belen never lost hope, it was with her until Pol’s dying breath. I see Jonah’s life in a different light now. 13 years into it and we have lost so many kids, kids that I met when Jonah was just a toddler. Pol and Elouan made me realize that Jonah had a lot of good years in front of him. Both boys were 4 years older than Jonah, seeing how well these boys were at 7 gave me so much hope for my boy. They put my mind at ease, they gave me the courage to fight Jonah’s fate, they led me to believe that Jonah had time. 

I’m very thankful that I was given so much hope when Jonah was diagnosed. Our researchers said if everything goes smoothly, we could have a treatment in 2 years. I needed to hear that, if I hadn’t, we wouldn’t be where we are today.

In 30 days, I will be turning 50.  Jeremy, Jonah and I are going to France, we’ll walk around Paris for a few days and then take a long road trip to the South of France. Sanfilippo Sud is having a fundraiser in Montauban on June 10^th which is my actual Birthday. https://www.facebook.com/donate/573221684916077/6244753015616517/

Afterwards Guilhain and Francine are putting us up for a few days, where I plan to sit in their lovely pool surrounded by good friends, family, and beautiful scenery. G&F live out in the country there isn’t another house in site. No cars, no construction, no hot summer city stench. My brain needs silence.

PN is working with Sanfilippo Sud and VML on a IIIC Natural History Study which is supposed to launch sometime relatively soon at Hospices Civils de Lyon. I’m getting super annoyed with how long the organizing and implementation of all the moving parts is taking. It’s a massive amount of work and going into another country adds another layer of applications and submissions. Meanwhile we’re hemorrhaging funds on trial management fees. Last May I went to France to meet with the funding organizations Sanfilippo Sud and VML to discuss the study. I also got to meet with the primary investigator of our NHS, Dr. Nathalie Guffon. That trip is in a previous blog.

Our IIID NHS launched in February, three patients have been seen and I just got word that 2 of our international patients plan on coming in June! I’m dang proud of the study.  Getting the first patient through in February was exhilarating! It still feels a bit surreal. It will be years before all the data is compiled and analyzed, so I'm trying not to dwell on the timeline. I have plenty of projects to keep me busy while we wait.

Allegedly we’re submitting the IIIC NHS protocol to the French ethics committee in a couple of weeks.  We were shooting for May 15^th, now they’re telling me that they must run our core informed consent forms back through review. The excuse being standard operation procedures call for it, the process could take another 2 weeks. I just can’t stand all the paper pushing. I’ll be 50 before this study gets started!

It pains me to say that our gene therapy program had yet another setback. We didn’t see a substantial behavioral change in our mouse study. We stepped back and took a hard look at the entire study design and the vector. We discovered that the assay used to measure the potency of the vector failed. Subsequently our animals were not dosed with a high enough concentration of drug. It’s been all hands on deck sorting out the issue and regrouping. Last month Alexey (Montreal) shipped several pairs of breeders (Hgsnat KO mice) to Steve Gray in TX. Steve is busy breeding another colony for dosing, I think the mice are capable of doing the dirty work themselves. A new highly concentrated batch of vector is being sent to TX from Spain today. Mice will start being dosed in 2 weeks, knock on wood, knowing our luck the vector will fall off a truck or they’ll forget the dry ice. I’m not going to sugar coat this, the timelines for getting into the clinic have been pushed out another two years. As hard as I try to keep a level head, I completely lost my cool when I found out what happened. I screamed fuck until I went hoarse, since then the women in the office next door hasn't made eye contact with me. I’m over it now, we know what the issue is, and it’s been addressed. The past is completely out of my control, and I need to let it go.

I have a new house/office plant hobby. For the most part when I feel helpless or ready to explode, I tend to my plants. Sometimes, I go downstairs to the little plant shop in my building and buy myself a new plant. I let it sit on the boardroom table, looking at it.  Repotting it and finding a home for it in my office is how I reward myself for addressing my latest work problem. 'Sometimes' define sometimes, the definition of sometimes has come up while creating our new Sanfilippo questionnaire. What does sometimes mean to you?  Is buying a plant once a week sometimes? To me it is. 'All the time' would be buying a plant everyday. Anyhow to each his own, we left out the option to choose sometimes as an answer in the questionnaire.

Our research is forever in need of funding you can donate to my Birthday fundraiser by clicking the link. Need I remind you it's also Mothers Day on Sunday?! MPS awareness day is on the 15th, which also marks the 13th year anniversary of Jonah's diagnosis. 

By the way, Jonah is doing absolutely fantastic! This is him, holding court at the playground, reading a book to the younger kids.

In loving memory of Pol.

Jonah's new word #Exhausted #CUREmps #GivingTuesday

Jonah’s new word.

 

I said I wasn’t going to write for a while because I’d be too busy. However, I’m still waiting for Columbia Presbyterian’s Internal Review Board (IRB) to come back with the green light so we can start enrolling patients for our IIID observational study! I’m growing more and more impatient as the days pass.  Thought I’d take a moment to hit you up for some cash. The 29^th is GivingTuesday and the Sanfilippo community is fundraising to help support our programs. https://www.facebook.com/donate/650264436504687/650264453171352/  Here is my fundraiser, if you don’t use Facebook, I applaud you and offer you an alternative way to donate. You can write a check to the Cure Sanfilippo Foundation, write Jonah in the memo line and post to: Cure Sanfilippo Foundation PO Box 6901 Columbia SC 29260

 

I’m constantly looking for evidence that Jonah is still learning. The other day Jonah and I were playing with his bat cave houses and figures, DC inspired doll houses and action figures. Jeremy and I use this activity to reinforce expressive and receptive communication. The DC characters knock on the bat cave door and greet whoever answers. We ask each other questions about what they’re doing today and encourage Jonah’s figure to ask us questions back. Jonah asked me where Wonder Woman and Harley Quinn were, I told him that they were having pizza at the pizzeria. I asked him how Superman was doing, Jonah responded, “Oh he’s exhausted.”

 

On one hand I was very proud of Jonah for using a new word on the other I felt super guilty for telling him how exhausted I am all the time. The next day I booked us a trip to the Adirondacks for the long Thanksgiving weekend. It was fabulous, I had the most glorious spa day, I hardly thought about work and completely ignored how much money we spent on treating me. Jeremy and I forced Jonah to go on a hike through the snow and rain and rewarded him with movies and peanut butter Nutella sandwiches. We found him a playground too! I didn’t spend two days cooking; all in all, we had a delightful time. Hope everyone else had a lovely day too.

I worry about Jonah more than usual; I see physical changes, he’s 14, it’s too be expected. I ask myself: has he always tripped in cracks or is this new? How long has he been coughing for? He doesn’t seem to hear half of what I’m saying. Jonah has new orthotics, he’s taken too them well. They slip into his shoes, so no one can see them, they help brace him, so his ankles don’t turn as easily. Jonah’s ankle turns on him frequently when he walks along the seam of the sidewalk or hits a dip or crack along the path. I cringe every time he does it. He yells at me I’m okay I’m okay mom. Writing about it makes me cry. He shouldn’t be tripping in a tiny crack. 

 

He coughs excessively after he eats, which is a sign of a swallowing issue. We finally got him an appointment to see a speech and eating expert to evaluate him. We’re going in tomorrow.  I’m hypersensitive of the swallowing issues as our kids predominantly die of aspiration pneumonia. Jonah doesn’t drool which is a good sign. We must get through the evaluation before they schedule the swallow study. I'm super anxious to find out if there is an issue or not.

His hearing has gotten me really worried too. Jonah wears his hearing aides all day at school. I let him take them off before he gets on the bus to come home. At first it was a precaution as to not loose them. If I’m being honest with myself, it’s more of an excuse to not have to fight with him at home to wear them. He constantly asks us what. I say his name when he’s not looking, and he doesn’t respond. He doesn’t hear the door open and shut when I come home. My next goal is to get him a sedated hearing test so we can find out the true extent of his hearing loss. If he can’t hear his ability to learn and comprehend will suffer. I’m wondering if a cochlear implant might be an option for him. 

I wanted to add some of these assessments to our IIID observational study, ALL-127. I had to let go of the sedated hearing and eye exam because it was too expensive. My team shot me down on the BARIUM swallow test sighting patient fatigue from all the assessments. Our kids can’t perform the typical hearing assessments, they don’t have the cognitive capabilities to answer the questions. Vision loss is another issue that we can’t assess as our kids can’t sit still long enough to take an image of the retina. I’m looking at the swallowing and gait issues from a neurological standpoint. Sanfilippo syndrome is primarily a syndrome of the Central Nervous System (CNS). The FDA wants to see neurological improvements after treatment. This is extraordinarily hard to deliver on our patient population. It would be easier to do if the syndrome wasn’t so rare. For instance, if we had 20 kids of the same age, speaking the same language and progressing at the same rate we’d have a cohort that was easier to draw conclusions from. 

 

The current way that cognitive function and expressive receptive language is assessed does not work for our, in part non-verbal, multiple languages and severely cognitively impaired population. The assessments used during most trials are not designed for such a diverse group of individuals. Furthermore, the assessments don’t come translated in all the different languages. To have an assessment translated you must first license the assessment, then pay to have someone translate it, then pay again to have the authors of the assessments approve the translations then pay for the certification of the translations to present to the IRB and FDA. Depending on the length of the test, this can easily end up costing $50,000 per language. For our trials we’re using the Leiter-3 which is designed for a non-verbal patient population, so I don’t have to pay to translate it to ten different languages. The drawback is that it won’t capture the receptive/expressive skills and it takes more expertise to administer.

To make up for the lack of standardized assessments available to use on our trials, my team created a protocol of activities of daily living (ADLs) that are to be filmed on a smart phone recording application. The app is called RARE (IIID) and C-RARE (IIIC) Recording Application for Real-world Evidence. The RARE app is hosted on Atom-5 and managed by the company, Aparito. The participants will be consented through our IRB approved protocol by the clinicians conducting the study. When the participants are on boarded, they will be given a code to download the app and a user manual explaining the study and instructions for recording the video tasks. The ADL tasks to be recorded are of the child performing the tasks in real-life under natural circumstances. The RARE app tasks are modeled after the domains of the typically used standardized assessments which are administer to the patient by the physician in a hospital.   

 

This project took a year to design, it is extensive and as clinical as we could make it without disturbing the child’s natural routine. We will capture the expressive/receptive language that the Leiter-3 doesn’t capture during the video tasks. All this will need to be scored by an independent panel of therapists and raters. I already feel like I'll be doing this project for the rest of my life. It's going to be epic!

We’re trying to capture and score the incremental changes of this slowly progressing CNS disorder. The video’s will be done over the same time-points of the child’s clinical visits at the hospital and every 6mo in between the site visits. The study will pick up again after the participant receives drug intervention. The ALL-127 Sanfilippo type D study design has been funded by our NIH/NINDS SBIR grant. It wasn’t a stretch to adapt it for IIIC. We’re now working on designing questionnaires to add to the C-RARE app. The C-RARE app questionnaires, instructions, and caregiver manual will need to be translated to numerous languages and the management of the app, scoring, and data collected still needs funding. However, the cost of creating our study from scratch still doesn’t even begin to compare to having to license and translate the assessments that are typically used for Sanfilippo trials. Fingers crossed it all works!

 

The mom that inspired me to create Phoenix Nest, Karen Aiach the CEO of Lysogene has released the most comprehensive results of her San A gene therapy trial to date. You can listen and watch the presentation here https://channel.royalcast.com/lysogene/#!/lysogene/20221123_1

 

It is very reassuring that the treatment has significantly impacted the progression of the syndrome in the little kids, under 30mo. It showed no difference on the primary endpoints for the older kids which is hard for our patient community to hear and accept (including me, Jonah is 14.) The primary endpoints included improvement of the scores of the cognitive assessments BSID-II and the KABS.  FYI, once a sponsor decides on a primary endpoint for their phase II/III interventional trial, they can't go back and change it. Once you choose it you're stuck with it and you must show that you improved the endpoint for drug approval. There is a lot of discussion around choosing the 'right' endpoint, but not enough discussion on how to measure that 'right' endpoint. 

I'm banking on findings provided by our RARE app and our different choices of clinical assessments to give us a deeper and clearer picture of the incremental improvements of the treated older patients. I believe we will also settle on a better 'right' endpoint and we will have better tools to measure our primary endpoint.  With any luck my grammar might improve one day too.

No matter what when our trials are completed and we have concrete evidence that the drug indeed works on the brains of pre-symptomatic children we will have a 'cure' for the next generation of kids. That is something to celebrate and I think Jonah would agree, he loves his friends deeply and hates to see anyone in distress. We have the sweetest kid ever, see for yourself. 

As always thanks so much for your continued support and Happy Holidays!

 

 To Donate go here:

 https://www.facebook.com/donate/650264436504687/

Cyclone

 

Coney Islands infamous Cyclone roller-coaster doesn’t hold a candle to my life. My life is so scary... How scary is it you ask?  It's so scary that I recently threw-up in my Dutch Bros cup.

 

Jonah attends school year-round. He has a small break at the end of summer before school starts up again.  I was torn between going to Oregon so he could have some family time or staying home so I could work. Jonah’s break coincides with one of the NIH/NINDS grant funding rounds. I had PTSD just thinking about being in Oregon last summer when our current grant was funded.

 

These grants are our community’s lifeline, I need to be able to drop everything to respond to an NIH/NINDS grant inquiry. The federal government takes them just as seriously. When you’re notified that your grant has been ‘recommended’ for funding you’re requested to submit numerous supporting documents. The process is called Just in Time (JIT), half of the supporting docs are regarding company financials. It’s basically like taking out a mortgage and closing on a house. The other half of the JIT articles relate to your grant’s specific aims.  You’re given a deadline to get everything in, if you miss it, you miss the funding round, hence the acronym JIT.  Last year’s grant included human participants, which involved getting certifications completed for JIT. It was intense and being 3 hours behind the east coast makes everything just a little bit harder. I knew if I went home this September that I could be in double trouble, but I went anyways.

 

Double trouble, we have potential funding coming in and we’re resubmitting the same grant just in case we don’t get awarded this time. Back story last spring, we won a grant, but funding was ‘deferred’. We received a great score, what they call an awardable score, but due to budget cuts only the perfect and near perfect scores got funded. Deferment meant that if another awardee did not make a milestone, then PN could get their funds. By September 5^th we’d find out if somebody missed their milestones so that our ‘deferred’ grant could be awarded. September 5^th was also the deadline for re-submission. Our program director told us to be prepared for both case scenarios.

 

PN’s Scientific Director, Sri does the grant writing, my job is to create the budget and gather the letters of support (LOS). It’s me that presses the submit button, so I need to be next to my computer and ready to trouble shoot error messages. I’ll tell you about error messages another day. I booked our tickets to Oregon and spent the next three days pulling together all the JIT articles that I knew they’d ask for and at the same time asked our collaborators for updated LOS. An outdated LOS or quote can give you bad marks on a submission and ultimately cost you the grant. Meanwhile Sri worked on updating quotes and adding in the new data. The second day into our trip to OR we received the letter acknowledging that our deferred grant had now been recommended for funding! JIT requests started coming in. At this point you’re still being warned not to get too excited, it’s not a done deal until the notice of award (NOA) is sent out.

 

One of the JIT requests questioned our use of a foreign research organization to manufacture our vector. The NINDS gave us 3 options the first was to find a US based manufacturer.  This is not something that can be done in a few days. The thought of even trying to make this happen was staggering. The wait times for vector manufacturing can be over a year, the work involved is extraordinarily detailed, it costs millions of dollars. Manufacturers need to have the blueprints to our construct; they must have internal meetings to discuss if their facilities can even do the work. The second option was to pay for the vector out of our own pocket, moot point. The third option was to submit a justification as to why we had to use the foreign component. I thought we had sufficiently justified the need for the foreign manufacturer in the body of our grant. If the reviewers didn’t think that justification was good enough, then what else could we say to them now?!

 

I talked to Sri first thing in the morning, he assured me that we had good justification, he reiterated our stance in a letter to NINDS and we submitted to JIT. The next question from NINDS was for the credentials of the foreign manufacturer, which is Viralgen by the way, they’re located in Spain.  Our grant program director said that funds going to Spain had to be approved by the State Department. Who says that? Well, who says that to little ole’ me anyways? I must get it approved by the State Department. Ha! She also informed us that approval could take a while. I thought to myself, no way we’re getting approval in time; good thing we re-submitted.

 

This was now the fourth time we submitted our gene therapy grant (JLK-247) for San C. The second time we submitted the grant it was kicked back due to ‘overstuffing’.  Overstuffing... we had included FDA comments that the grant submission portal ‘gatekeeper’ (for the lack of a better title) said to be against grant rules. Our justification for doing this was because the first time we submitted the grant and didn't win, the reviewers commented that they’d like to see if the study design had FDA buy-in (I’m paraphrasing). We went to the FDA, received the nod, and included their comments regarding our study design to the grant as a letter of support and resubmitted. The gatekeeper did not like that approach and accused us of trying to get around the grant page limit by adding in FDA comments as a LOS. For the record we also added the comments in the body of the grant. We included the official comments as a LOS because we thought it was a nice touch and our program director agreed.

 

Sri and I fought for the grant to be permitted through and asked to let us go with a warning. She could have redacted the portion of the FDA comments that she felt were unfair (I'm pretty sure she actually used the word egregious) to the other applicants. It was a heated conversation. The gatekeeper demanded that I put in writing my justification as to why I was so special that I got to cheat (I’m not paraphrasing). At this point I was foaming at the mouth.  I have a consultant that advises us on grant submissions, he highly recommended that I drop it, that I was not going to win this argument. I let it go and we resubmitted four months later at the following submission date; this is the grant that got deferred.

 

Not that we have come full circle, did we win the grant or not?  I don’t know, I do know that the State Department approved our justification to working with Viralgen!  I’m thrilled but trying to temper my expectations. I think we’re just waiting on the OLAW (Animal Welfare Assurance) confirmation now; we sent it in on Thursday but no response if it was enough. Radio silence.

 

There have been a handful of diagnosed San C patients this year. It’s always how long how long how long. I respond I don’t know, it’s not up to me. That doesn’t stop them from asking. I don’t blame them; I know exactly how they feel. What brings me to tears is the overwhelming feeling of helplessness, drug development does not come with a GPS! I'm trying to go as fast as I can families.

 

The grant funds will cover the study that analyzes the tissue from the mouse dosage study using our new vector (JLK-247) this study was supported in part by the Cure Sanfilippo Foundation. Among other things we will be looking at the biodistribution of JLK-247. If it and everything else is good, then we can go to the FDA and ask if we can go to trial. If they’re not convinced, we’ll have to do another animal study.

 

It has been an extraordinarily busy year. The grant that was awarded this time last year is funding for the Natural History Study (NHS) protocol design and implementation of Sanfilippo syndrome type D, the program name is ALL-127. I’ll spare you the gory details of securing that funding and skip to the exciting part. Writing a clinical protocol 101: Patient input matters more than most sponsors imagine. The FDA talks about how important patient engagement is for selecting endpoints and trial design every chance they get. I’m not getting the sense that sponsors have really understood or taken to heart that message. They can’t just send out a survey asking families what the biggest burdens are. That isn’t good enough.

 

Patients need a seat at the table, not just metaphorically but literally. We need to have a say in how the symptoms are measured. Some symptoms (endpoints) are easy to measure- straight forward. In the case of Sanfilippo there is not one endpoint that is straight forward or easy to measure. Which is mind-blowing because the syndrome affects every system of the body. It hits the central nervous system (CNS) the hardest, a hit to the CNS radiates out to the all the other bodily systems.  Affecting the way our kids: walk, talk, eat, think, sleep pee/poop, process sensory input and behave. The children’s other organs are affected as well but the impacts are subtle and don’t cause immanent death. Unless their lungs fill with fluid from pneumonia, which doesn't make for a good endpoint either.

 

For the Sanfilippo community communication and mobility are two of the top-ranking symptoms. Improvement in communication gets lost in translation to sponsors. We can’t just say improvement in communication to a sponsor. The sponsors think speech. A parent of a Sanfilippo child sets the communication bar much lower. We want our kids to be able to communicate non-verbally, it can be as simple as a smile. A smile from our kids means everything to us. Think about it, what if your loved one stopped smiling? Will the FDA approve a million-dollar drug for smiles? A million-dollar smile, totally worth it 😊.  

 

In the case of Sanfilippo, sponsors have leaned on cognitive tests for measurement of treatment improvement, think of the SAT. These types of assessments are guarded by the authors and license holders. To see them you must have your clinical team lined up and prove your intent of conducting a clinical trial. When we first wrote the grant, we had to include a synopsis of our intended clinical protocol for ALL-127. We chose assessments that were used in the other clinical trials for San A and B. At this point I had still not gained access to the cognitive assessments. It wasn’t until after the grant was awarded and our site and clinicians had been secured that I was permitted to see the assessments. By then we had finalized our protocol and sent it in for IRB approval, this was no small feat. 

 

After reviewing the assessments well if you can’t guess by now… I was nauseous and plagued with doubts.  The assessments in my opinion were not appropriate for the Sanfilippo patient population. At the same time, our FDA comments came back, they had reviewed our protocol and had numerous suggestions regarding out choice of cognitive assessments. The final straw was the results from the failed and divested San A and B drug trials that were finally being published. The data suggested further that the chosen cognitive assessments were not appropriate to measure their endpoints. Our ALL-127 protocol had literally just received IRB approval; we could start recruiting patients soon. We were faced with a major decision- continue with the status quo or start over. We started over. Now we were faced with missing a milestone and not  having funds released in time to continue study startup. It’s a non-stop roller-coaster ride. I can’t say I never catch a break; the break was getting the chance albeit a last-minute chance to right a wrong. We were left with now trying to find the assessments that would work.

 

As mentioned, you can’t go to a library or store and browse through all the assessments available to license and use in trials. We must work with the companies that own them. They have specialists that help you zero in on topics of interest, I combed through endless assessments. Nothing was right. I called on Jonah’s therapists. Who better to point me in the right direction then the teachers on the front lines administering these tests to kids like Jonah. His therapists gave me a list of tests, which I then requested to view from the owners. My guy chuckled when he pulled them for me. He said he wasn’t even aware that they owned the assessments, they were so old. On that note… I finally had something we could work with. The ALL-127 protocol is now finished and back with the hospitals Internal Review Board (IRB). We anticipate approval to be coming in a few weeks. Our site initiation visit is set for October 14^th. Our goal for first patient in is end of October early November. We will make our first milestone and be able to bring the rest of the participants in for screening and baseline after the new year. After that the participants will come in for two more annual visits.  Meanwhile the ERT mouse toxicology studies for ALL-027 will wrap up and we will head back to the FDA. If all goes smoothly the ALL-127 patients will proceed into the interventional trial. Truth be told I’d like to extend the study for at least a third year, sadly we don’t have the budget for it.

 

The study is extraordinarily expensive. Our hope is that once we start accumulating the natural history data that we will garner more pharma interest and find a financial partner. I have a feeling that once the study is published on clinicaltrials.gov that we will have more patients wanting to participate. It would be amazing if we could include all the San D kids that wanted to come. The participants are coming from around the world, over half of them don’t speak English. We must translate all the consents and other patient facing documents to their native languages and bring in translators to help them throughout the study. ALL-127 doesn’t just include cognitive assessments, there are numerous physical and clinical tests as well.  Labs, sedation for x-rays and MRI. It’s no walk in the park for the children or their parents. Their commitment to the study and desire to help bring forth a treatment is nothing less than heroic. 

 

The ALL-127 protocol is going the extra mile by including a video collection of daily living activities (ADLs) shot at home by the children’s caregivers.  There will be a retrospective portion as well, all the patients’ medical records will be reviewed for the onset of disease symptoms. All the data gets imputed by the site coordinator into a controlled data base. It took our team (Labcorp) almost a year just to design the database, in their defense I did keep making changes to the protocol.

  

I’m extremely proud of the video portion of the study, we’re working with Aparito, a company that has licensed HIPPA and GDPR compliant software program to manage patient data. With the help of our patient community our team came up with several activities that we hope will capture the participants real-time real-world experiences. Caregivers will video children performing daily activities in a natural setting, within standardized parameters for video capture which will hopefully cause minimal disruption in their daily routines. The video activities compliment the assessments performed in the clinic. The idea is to visualize, describe and score the children’s behavior, movement, communication abilities, and yes smiles that are hard or even impossible to capture in the clinic. Remember our young kids are always on the move, they can’t sit still and tend to run away. Our advanced kids smile if we're lucky, they're cared for 247. I'm hoping that our video tasks will capture a few smiles and any incremental improvements seen by families after intervention.

 

These videos are taken on a smart phone using an app, the families are given a secure QR code where they download the app, which has been designed and translated to walk them through all the activities and questionnaires. The videos will be taken within 14 days of the clinical visits and at 6mo time points in between the clinic visits. We named the app RARE Recording Application for Real-world Evidence. The San C version is called C-RARE, get it? Sri came up with the acronyms.

 

When supporters donate to medical research, the primary thought is the cost and time of drug discovery in the lab. This is the tangible portion that can be visualized. It’s the behind the scenes and back-end work that you don’t see that takes just as much time and funding resources as the laboratory research. The contracts, study design and quality checks are sucking up all my time. Everything that goes into drug discovery must be meticulously collected, scored, and stored for FDA review.

 

In between reviews I have been working on new quality of life and clinical outcome questionnaires tailored to absorb as much as we can out of the Sanfilippo patient experience. These types of questionnaires are called Clinical Outcome Assessments (COAs) the cognitive assessments also fall under the COAs. Over the past ten years I have been told on numerous occasions that it is too hard to design and validate syndrome specific COAs. That I’d be wasting time to even try because the FDA wanted the ‘gold standard’ validated assessments that have been used in thousands of trials. It later occurred to me that the advice was coming from people that didn’t have a full understanding of the progression or phenotype of Sanfilippo syndrome or that the FDA had extremely little experience with Sanfilippo. It’s only been 10 years since the very first San A trial started. The FDA is just now wrapping their brains around the data coming from these trials. They have had a steep learning curve. 

 

A few months ago, the FDA came out with a new guidance that states if there is not an assessment available that is sensitive enough to measure your target endpoint, then make a new assessment, they go on to walk you through how to do it. I had already started to create a COA to measure behavior when this guidance came out. The FDA guidance was the push I needed to create a series of Sanfilippo specific COAs. The Sanfilippo families have been guiding us on the development of these COAs, patiently walking through every question and giving their feedback and suggestions for improvement. It has been an extremely rewarding experience for all of us.  My team engsged a couple of expert clinical assessment designers to help us with the scoring and wording of the questionnaires. When finished we’re going to pilot the COAs on the C-RARE app. We didn't finish the new COAs in time for the ALL-127 launch. They will however be done by the ALL-027 intervention trial.

 

The JLK-347 clinical protocol is being scrubbed by Labcorp’s quality control team right now!  Labcorp is the CRO managing our studies and storing the data.  We’re planning 2 sites, one in France and the second in the US. While the NHS for San C gets underway, we will finish up the tox and biodistribution animal studies (contingent on the grant coming in). The plan is for JLK-347 participants to transition straight into the interventional trial, JLK-247 and become their own controls. 

 

PN has been working on a third program that is suitable for all Sanfilippo subtypes, AVP6. It’s a peptide administered nasally which increases synaptic function. It’s an option that will pair nicely with gene therapy and ERT interventions.

 

I have taken the time to give you all an extra-long blog as I plan on being too busy to write again for another year! Tomorrow we will win the JLK-247 grant and begin our next chapter. Watch for the press release on Linkedin.Fingers crossed.

 

Quick Jonah update, he is doing great! He's still smiling and still learning. He just started his freshman year! Jeremy and I are so incredibly proud of him. This kid is fighting his fate like, Batman, his favorite superhero and he doesn't even know it.

 

 

I gave a few talks this year:

ADVANCE Sanfilippo syndrome workshop Cure Sanfilippo Foundation   

https://www.youtube.com/watch?v=UbtxDl20TyQ&t=3s                                      

My talk is on the ALL-127 program and RARE app. It starts at 1:30ish.  Phoenix Nest had three other talks. Srikanth Singamsetty discusses JLK-247, Tsui-Fen Chou speaks about ALL-127 and Alexey Pshezhetsky gave a talk on AVP6. The AVP6 talk and it's data were not published for wide distribution. You will have to wait until we publish.

NINDS Nonprofit Forum 2022

https://videocast.nih.gov/watch=45549

My talk starts at 2:17ish on day 1. Please watch the talk right after mine with Emily Caporello, NINDS and put a face with my "program director".

Decision Vision Podcast

https://businessradiox.com/podcast/north-fulton-studio/decision-vision-apply-for-grants-jonahs-just-begun-sanfilippo/

I spoke on my experience with applying for NINDS SBIR/STTR grants

 

RDLA- Rare Disease Week 2022- Policy Deep Dive: Speeding Therapy Access Today (STAT)act

https://www.youtube.com/watch?v=btB0cCzWoM8 

Spoke to how federal funding helps the ultra-rare disease community! My talk starts at 1ish

Check out the new FDA fit-for-purpose clinical outcome assessment guidance.

https://www.fda.gov/media/159500/download